Pro-Oncogenic Role of a Mitochondrial Lipid Kinase in CLL

线粒体脂质激酶在 CLL 中的促癌作用

• 批准号: 10651077
• 负责人: Asish Kumar Ghosh
• 金额: $ 16.95万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-10 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10651077
• 关键词: Accounting; Adult; Agammaglobulinaemia tyrosine kinase; Antigens; Applications Grants; Automobile Driving; B lymphoid malignancy; B-Cell Activation; B-Cell Antigen Receptor; B-Lymphocytes; BCL2 gene; Behavior; Binding; Biological; Biological Process; Blood; Bone Marrow; Cell Proliferation; Cell Survival; Cells; Cellular biology; Cervical Squamous Cell Carcinoma; Chronic Lymphocytic Leukemia; Clinical; Cytoplasm; Data; Dedications; Diagnosis; Diglycerides; Disease; Disease Progression; Early treatment; Epigenetic Process; Esophageal Squamous Cell Carcinoma; Event; FRAP1 gene; Genetic; Genetic Transcription; Goals; Heterogeneity; Human; In Vitro; Indolent; Induction of Apoptosis; Investigation; JAK2 gene; LYN gene; Lipids; Liposomes; Malignant - descriptor; Malignant neoplasm of prostate; Mediating; Mediator; Mitochondria; Molecular; Monoglycerides; Nuclear; Oncogenes; Oncogenic; Oral; Organ; PI3K/AKT; PIK3CG gene; PTEN gene; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Phosphatidic Acid; Phosphotransferases; Process; Production; Proliferating; Proto-Oncogene Proteins c-akt; Public Health; Receptor Inhibition; Receptor Signaling; Regulation; Resistance; Richter' s Syndrome; Risk Factors; Role; STAT3 gene; Signal Transduction; Signaling Molecule; Small Interfering RNA; Spleen; Squamous cell carcinoma; Testing; Therapeutic; Time; Transgenic Mice; Treatment outcome; Tumor Burden; Up-Regulation; cell growth; cell type; chronic lymphocytic leukemia cell; clinical heterogeneity; cohort; cytotoxic; high risk; improved; in vivo; inhibitor; inhibitor therapy; innovation; insight; kinase inhibitor; large cell Diffuse non-Hodgkin' s lymphoma; leukemia; lymph nodes; lysophosphatidic acid; malignant breast neoplasm; mitochondrial membrane; mouse model; novel; overexpression; prognostic; relapse patients; survival outcome; targeted agent; targeted treatment; therapeutic target; therapy outcome; therapy resistant; tumor; tumorigenesis

PROJECT SUMMARY Chronic lymphocytic leukemia (CLL) is an adult B-cell malignancy accounting for about a third of leukemia diagnoses in the US. While B-cell receptor (BCR)-signal-inhibitors are changing the management of CLL, these are not curative and resistance can develop; often leading to more aggressive disease. Given this, understanding the molecular events driving CLL oncogenesis and therapeutic resistance warrants in-depth investigation. CLL is a disease characterized by extensive clonal proliferation and accumulation of malignant B lymphocytes in the blood, bone marrow, spleen, and lymph nodes. CLL shows remarkable clinical heterogeneity, with some patients pursuing an indolent course, while others progress rapidly and require early treatment. In the past 10 years, new insights into the biological function of a mitochondrial lipid kinase, acylglycerol kinase (AGK), as a key oncogene that is highly expressed in a range of tumor types, including prostate cancer, breast cancer, cervical squamous cell carcinoma, and esophageal squamous cell carcinoma have been established. Most recently, we found aberrantly high level expression of AGK in CLL cells from ~60% of pre-therapy CLL patients. However, the mechanism of aberrant upregulation of AGK in CLL cells, and its precise functional contributions to CLL cell biology and pathogenesis remain unknown. Interestingly, we detected nuclear/cytoplasmic localization of AGK in some CLL clones suggesting its multi-functional role. In line with this, we found that siRNA- mediated depletion of AGK in primary CLL cells resulted in marked inhibition of constitutively active multiple signal mediators including AKT, Erk1/2, LYN, BTK (downstream targets of BCR signal) and JAK2. Our preliminary findings also indicate that MYC may regulate AGK expression in CLL cells. Our combined data suggest that aberrant expression of AGK may potentiate cell survival signals including BCR and JAK2 in some CLL clones resulting in resistance to BCR-targeted therapies. Therefore, the central hypothesis of this application is that aberrant expression of AGK in some CLL clones represents highly aggressive CLL with shorter time to therapy. We also postulate that AGK upregulation potentiates CLL cell survival signals and resistance to BCR- targeted agents. We propose – Aim 1: Evaluate if aberrant expression of AGK in CLL cells drives disease progression; Aim 2: Define the mechanism of AGK upregulation and its role in CLL cell biology, signaling and potential as a therapeutic target. The proposed in-depth studies will assess if “high AGK” level in CLL cells serves as a risk factor for CLL progression, time to therapy and treatment outcome; define the impact of AGK aberrant expression on CLL cell survival and resistance to current BCR-targeted therapies. Thus, the proposed studies have enormous potential to establish a new prognostic parameter and therapeutic avenue via targeting AGK in CLL cells with or without the current BCR-targeted therapy, ibrutinib.

项目摘要 慢性淋巴细胞白血病是一种成人B细胞恶性肿瘤，约占白血病的三分之一 在美国的诊断虽然B细胞受体（BCR）信号抑制剂正在改变CLL的管理，但这些药物可能会影响CLL的治疗。 不能治愈，并且会产生抗药性;通常会导致更具侵略性的疾病。鉴于此，理解 驱动CLL肿瘤发生和治疗抗性的分子事件值得深入研究。 CLL是一种以恶性B淋巴细胞广泛克隆性增殖和聚集为特征的疾病 在血液骨髓脾脏和淋巴结里CLL显示出显著的临床异质性，其中一些 病人追求无痛过程，而其他人进展迅速，需要早期治疗。过去10 近年来，对线粒体脂质激酶--酰基甘油激酶（AGK）的生物学功能有了新的认识， 在一系列肿瘤类型中高度表达的关键癌基因，包括前列腺癌，乳腺癌， 宫颈鳞状细胞癌和食管鳞状细胞癌已经确立。最 最近，我们在约60%的治疗前CLL患者的CLL细胞中发现异常高水平的AGK表达。 然而，CLL细胞中AGK异常上调的机制及其确切的功能贡献 CLL的细胞生物学和发病机制仍然未知。有趣的是，我们检测到细胞核/细胞质 AGK在一些CLL克隆中的定位表明其多功能作用。与此一致，我们发现siRNA- 在原代CLL细胞中介导的AGK消耗导致组成性活性多个细胞因子的显著抑制， 信号传导介质包括AKT、Erk 1/2、林恩、BTK（BCR信号传导下游靶点）和JAK 2。我们 初步发现也表明MYC可能调节CLL细胞中AGK的表达。我们的综合数据 提示AGK异常表达可能在某些情况下增强细胞存活信号，包括BCR和JAK 2， CLL克隆导致对BCR靶向疗法的抗性。因此，本申请的中心假设 某些CLL克隆中AGK的异常表达代表高度侵袭性CLL， 疗法我们还假设AGK上调增强CLL细胞存活信号和对BCR-1的抗性。 目标代理人目的1：评估CLL细胞中AGK的异常表达是否驱动疾病 目的2：确定AGK上调的机制及其在CLL细胞生物学、信号传导和免疫调节中的作用。 作为治疗靶点的潜力。拟议的深入研究将评估CLL细胞中的“高AGK”水平是否有助于 作为CLL进展、至治疗时间和治疗结局的风险因素;定义AGK异常的影响 表达对CLL细胞存活和对当前BCR靶向疗法的抗性的影响。因此，拟议的研究 通过靶向AGK，具有建立新的预后参数和治疗途径的巨大潜力， CLL细胞与或不与目前的BCR靶向治疗，伊曲替尼。